Granted Patent B2

US 12,421,240 · App. 17/772,930 · Granted Sep 23, 2025

Inventors: Hongtao Xu (Shanghai, CN); Zhisen Zhang (Shanghai, CN); Wei Zhu (Shanghai, CN); Ge Zou (Shanghai, CN)

Assignee: Hoffmann-La Roche Inc.

C07D487/04C07D519/00

Abstract

Claims (115)

1. A compound of formula (I),

wherein

R 1 is

wherein R 4 is C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, halogen, nitro or cyano; R 4a is C 1-6 alkyl or C 3-7 cycloalkyl; R 5 , R 5a and R 5b are independently selected from H and deuterium; and R 6 is H or halogen;

R 2 is C 1-6 alkyl;

R 3 is a 5-7 membered monocyclic aryl or heteroaryl; or a 7-12 membered bicyclic heterocyclyl; and

n is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein

R 3 is 1,2,3,4-tetrahydroisoquinolinyl;

5,6,7,8-tetrahydro-1,6-naphthyridinyl;

5,6,7,8-tetrahydro-1,7-naphthyridinyl;

5,6,7,8-tetrahydro-2,6-naphthyridinyl;

5,6,7,8-tetrahydro-2,7-naphthyridinyl;

phenyl substituted by morpholinyl;

pyrazinyl substituted by piperazinyl;

pyridinyl which is substituted by one or two substituents independently selected from halogen, piperazinyl, aminohalopyrrolidinyl, amino-1,4-oxazepanyl and amino (C 1-6 alkoxy) pyrrolidinyl; or

pyrimidinyl substituted by piperazinyl or amino (C 1-6 alkoxy) pyrrolidinyl.

3. A compound according to claim 1 , wherein

R 1 is

wherein R 4 is cyano; and R 5 is H;

R 2 is C 1-6 alkyl;

R 3 is 5,6,7,8-tetrahydro-2,6-naphthyridinyl; 5,6,7,8-tetrahydro-2,7-naphthyridinyl; pyridinyl substituted by amino (C 1-6 alkoxy) pyrrolidinyl; or pyrimidinyl substituted by piperazinyl; and

n is 0 or 1;

or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 3 , wherein

R 1 is

wherein R 4 is cyano; and R 5 is H;

R 2 is methyl;

R 3 is 5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl; 5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl;

piperazin-1-ylpyrimidinyl; or 3-amino-4-methoxy-pyrrolidin-1-ylpyridinyl; and

n is 0 or 1;

or a pharmaceutically acceptable salt thereof.

5. A process for the preparation of a compound according to claim 1 , comprising any one of the following steps:

a) Buchwald-Hartwig amination reaction or nucleophilic substitution between compound of formula (IX),

and amine (X),

b) Buchwald-Hartwig amination reaction or nucleophilic substitution between compound of formula (V),

and compound of formula (VI),

wherein R 1 and R 2 are as defined in claim 1 ; n is 0, 1 or 2; X is halogen; Y is halogen or methanesulfonate; R 7 and R 8 is aryl or heteroaryl; and R 9 and R 10 together with the nitrogen atom they are attached to form a heterocyclyl.

6. A pharmaceutical composition comprising a compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

7. A method for the treatment of systemic lupus erythematosus or lupus nephritis in a mammal in need thereof, which method comprises administering a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to said mammal.

8. A compound of formula (Ia),

wherein

R 1 is

wherein R 4 is C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, halogen, nitro or cyano; R 4a is C 1-6 alkyl or C 3-7 cycloalkyl; R 5 , R 5a and R 5b are independently selected from H and deuterium; and R 6 is H or halogen;

R 2 is C 1-6 alkyl;

R 3 is 1,2,3,4-tetrahydroisoquinolinyl;

5,6,7,8-tetrahydro-1,6-naphthyridinyl;

5,6,7,8-tetrahydro-1,7-naphthyridinyl;

5,6,7,8-tetrahydro-2,6-naphthyridinyl;

5,6,7,8-tetrahydro-2,7-naphthyridinyl;

phenyl substituted by morpholinyl;

pyrazinyl substituted by piperazinyl;

pyridinyl which is substituted by one or two substituents independently selected from halogen, piperazinyl, aminohalopyrrolidinyl, amino-1,4-oxazepanyl and amino (C 1-6 alkoxy) pyrrolidinyl; or

pyrimidinyl substituted by piperazinyl or amino (C 1-6 alkoxy) pyrrolidinyl; and

n is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 8 , or a pharmaceutically acceptable salt thereof, wherein

R 1 is

wherein R 4 is cyano; R 4a is C 1-6 alkyl; R 5 is H; and R 6 is H or halogen; and

n is 0 or 1.

10. A compound according to claim 9 , wherein

R 1 is

wherein R 4 is cyano; R 4a is methyl; R 5 is H; and R 6 is H or fluoro;

R 2 is methyl;

R 3 is 1,2,3,4-tetrahydroisoquinolin-6-yl;

1,2,3,4-tetrahydroisoquinolin-7-yl;

5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl;

5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl;

5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl;

5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl;

5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl;

5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl;

morpholin-2-ylphenyl;

piperazin-1-ylpyrazinyl;

pyridinyl which is substituted by one or two substituents independently selected from fluoro, piperazin-1-yl, 3-amino-4-fluoro-pyrrolidin-1-yl, 6-amino-1,4-oxazepan-4-yl and 3-amino-4-methoxy-pyrrolidin-1-yl; or

pyrimidinyl substituted by piperazin-1-yl or 3-amino-4-methoxy-pyrrolidin-1-yl; and

n is 0 or 1;

or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 1 is

wherein R 4 is cyano; and R 5 is H.

12. A compound according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 3 is 5,6,7,8-tetrahydro-2,6-naphthyridinyl; 5,6,7,8-tetrahydro-2,7-naphthyridinyl; pyridinyl substituted by amino (C 1-6 alkoxy) pyrrolidinyl; or pyrimidinyl substituted by piperazinyl.

13. A compound according to claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 3 is 5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl; 5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl; piperazin-1-ylpyrimidinyl; or 3-amino-4-methoxy-pyrrolidin-1-ylpyridinyl.

14. A compound selected from:

5-[(4R,10aS)-4-methyl-8-(6-piperazin-1-yl-3-pyridyl)-1,3,4,6,7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile;

5-[(4R,10aS)-4-methyl-8-(2-piperazin-1-ylpyrimidin-5-yl)-1,3,4,6,7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile;

5-[(4R,10aS)-4-methyl-8-[4-[(2S)-morpholin-2-yl]phenyl]-1,3,4,6, 7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile;

5-[(4R,10aS)-4-methyl-8-(5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl)-1,3,4,6,7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile;

5-[(4R,10aS)-4-methyl-8-(5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)-1,3,4,6,7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile;

5-[(4R,10aS)-4-methyl-8-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-1,3,4,6,7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile;

5-[(4R,10aS)-4-methyl-8-(5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)-1,3,4,6,7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile;

5-[(4R,10aS)-4-methyl-8-(5,6,7,8-tetrahydro-2,7-naphthyridin-3-ylmethyl)-1,3,4,6,7,9,10, 10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile;

5-[(4R,10aS)-4-methyl-8-(5,6,7,8-tetrahydro-2,6-naphthyridin-3-ylmethyl)-1,3,4,6,7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile;

5-[(4R,10aS)-4-methyl-8-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-ylmethyl)-1,3,4,6,7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile;

5-[(4R,10aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-6-ylmethyl)-1,3,4,6,7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile;

5-[(4R,10aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-7-ylmethyl)-1,3,4,6,7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile;

5-[(4R,10aS)-4-methyl-8-[(5-piperazin-1-ylpyrimidin-2-yl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile;

5-[(4R,10aS)-4-methyl-8-[(2-piperazin-1-ylpyrimidin-5-yl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile;

5-[(4R,10aS)-4-methyl-8-[(5-piperazin-1-ylpyrazin-2-yl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile;

5-[(4R,10aS)-4-methyl-8-[(5-piperazin-1-yl-3-pyridyl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile;

5-[(4R,10aS)-4-methyl-8-[(6-piperazin-1-yl-3-pyridyl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile;

5-[(4R,10aS)-4-methyl-8-[(6-piperazin-1-yl-2-pyridyl)methyl]-1,3,4,6,7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile;

5-[(4R,10aS)-4-methyl-8-[(5-piperazin-1-yl-2-pyridyl)methyl]-1,3,4,6,7,9, 10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile;

5-[(4R,10aS)-8-[[5-[(3R,4S)-3-amino-4-fluoro-pyrrolidin-1-yl]-2-pyridyl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile;

5-[(4R,10aS)-8-[5-[(6R)-6-amino-1,4-oxazepan-4-yl]-2-pyridyl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile;

5-[(4R,10aS)-8-[[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-2-pyridyl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile;

5-[(4R,10aS)-8-[(3-fluoro-5-piperazin-1-yl-2-pyridyl)methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile;

5-[(4R,10aS)-8-[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-fluoro-2-pyridyl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]quinoline-8-carbonitrile;

4-[(4R,10aS)-8-[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]pyrazin-2-yl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

4-[(4R,10aS)-8-[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-fluoro-2-pyridyl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

4-[(4R,10aS)-8-[5-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3-fluoro-2-pyridyl]methyl]-4-methyl-1,3,4,6,7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile; and

4-[(4R,10aS)-4-methyl-8-(1,2,3,4-tetrahydroisoquinolin-7-ylmethyl)-1,3,4,6,7,9,10,10a-octahydropyrazino [1,2-d][1,4]diazepin-2-yl]-1-methyl-1,8-naphthyridin-2-one;

or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound in accordance with claim 14 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

16. A method for the treatment of systemic lupus erythematosus or lupus nephritis in a mammal in need thereof, which method comprises administering a therapeutically effective amount of a compound according to claim 14 , or a pharmaceutically acceptable salt thereof, to said mammal.

Assignments (3)

Priority Claims (1)

Continuity (1)

References Cited (73)